1. Field of the Invention
The present invention relates generally to the fields of cancer therapy and gene therapy. More particularly, it concerns the use of p202 to prevent and treat cell transformation.
2. Description of Related Art
Oncogenesis was described by Foulds (1958) as a multistep biological process, which is presently known to occur by the accumulation of genetic damage. On a molecular level, the multistep process of tumorigenesis involves the disruption of both positive and negative regulatory effectors (Weinberg, 1989). The molecular basis for human colon carcinomas has been postulated, by Vogelstein and coworkers (1990), to involve a number of oncogenes, tumor suppressor genes and repair genes. Similarly, defects leading to the development of retinoblastoma have been linked to another tumor suppressor gene (Lee et al., 1987). Still other oncogenes and tumor suppressors have been identified in a variety of other malignancies. Unfortunately, there remains an inadequate number of treatable cancers, and the effects of cancer are catastrophic--over half a million deaths per year in the United States alone.
Cancer is fundamentally a genetic disease in which damage to cellular DNA leads to disruption of the normal mechanisms that control cellular proliferation. Two of the mechanisms of action by which tumor suppressors maintain genomic integrity is by cell arrest, thereby allowing for repair of damaged DNA, or removal of the damaged DNA by apoptosis (Ellisen and Haber, 1998; Evan and Littlewood, 1998). Apoptosis, otherwise called "programmed cell death," is a carefully regulated network of biochemical events which act as a cellular suicide program aimed at removing irreversibly damaged cells. Apoptosis can be triggered in a number of ways including binding of tumor necrosis factor, DNA damage, withdrawal of growth factors, and antibody cross-linking of Fas receptors (Cohen, 1993; Lowe et al., 1993; Sentman et al., 1991; Smith et al., 1994; Suda et al., 1993; Williams and Smith, 1993). Although several genes have been identified that play a role in the apoptotic process, the pathways leading to apoptosis have not been fully elucidated.
Interferons (IFNs), a family of cytokines, consists of three major glycoproteins, INF-.alpha., INF-.beta., and INF-.gamma.. IFNs possess a wide variety of biological properties such as anti-virus, anti-proliferation, immunoregulation, anti-angiogenesis, and anti-neoplasia (Gutterman, 1994). The anti-neoplastic activity of IFNs can be attributed, in part, to their anti-proliferation function and the activation of host defense systems on tumor cells. In addition, the demonstration of anti-angiogenic activity of IFNs has led to clinical trials using IFN treatment for vascular tumors, that include Kaposi sarcoma (Oettgen et al., 1986), pulmonary hemangiomatosis (Grzegorzewski et al., 1989) and hemangioma (Ezekowitz et al., 1992), resulting in tumor regression in these patients. Apart from the therapeutic effects of IFNs in certain clinical settings, there were also undesirable side effects (e.g., fever, chills, anorexia, and anemia) associated with the high dose IFN treatment often required to obtain a significant response (Ahre et al., 1998; Kirkwood et al., 1985).
p202 is a 52 kDa nuclear IFN-inducible phosphoprotein. This protein may inhibit the transcription of certain genes by interacting with various transcription modulators (Choubey et al., 1996; Choubey et al., 1997; Choubey and Lengyel, 1995; Datta et al., Datta et al., 1998; 1996; Min et al., 1996). p202 expression has been associated with an increase in both p21 and Rb and a decrease in Cdk2 protein kinase activity (Gutterman and Coubey, 1999) and constitutive expression of p202 may be associated with cell cycle arrest in mammalian cells (Lembo et al., 1995; Yan et al., 1999).